An increased endogenous synthesis of oxalate is the underlying cause of the rare genetic disease, primary hyperoxaluria. This disease can be fatal due to renal failure and oxalate deposition in tissues, particularly if it manifests during infancy. Endogenous oxalate synthesis may also play a role in idiopathic calcium oxalate nephrolithiasis and decreasing the amount synthesized could be an effective therapeutic strategy. Despite the clinical significance of endogenous oxalate synthesis, the biosynthetic pathways that lead to its synthesis are largely unknown. The long-term goals of this research project are to define the pathways involved in oxalate synthesis and to develop therapies that will effectively reduce it. The specific aims of this proposal have been developed to determine which sugars and amino acids contribute to oxalate synthesis, to identify the metabolic pathways involved, and to gain an insight into the regulation of these synthetic pathways. Our research will utilize a recently developed technique, ion chromatography coupled with mass detection (IC/MS), to pursue these specific aims. This technique will allow the use of stable isotopes of sugars and amino acids to determine whether their catabolism leads to oxalate synthesis. Experiments will be conducted in cultured cells and in human subjects infused with isotopes to examine this catabolism. Culture media, blood and urine will be assayed by IC/MS and other procedures. The effects of hormones, principally glucagon, on these catabolic pathways will be examined to elucidate their regulation. These experiments will increase our understanding of the steps involved in endogenous oxalate synthesis and may lead to better therapies to treat individuals with the primary hyperoxalurias and with calcium oxalate stone disease. Primary hyperoxaluria is a rare genetic disease that can significantly alter the health of affected individuals and cause a life-long concern for them and their families. Understanding the reactions that occur in the body to cause this disease could lead to the design of better treatments, not only for individuals with this disease, but possibly for those who suffer from the much more prevalent calcium oxalate stone disease.